Simian immunodeficiency virus (SIV) infection of macaques provides the best non-human primate model for studying AIDS. These investigators will utilize the SIV/macaque model to determine whether nef-specific cytotoxic T lymphocytes (CTL) play a role in selection for new virus variants in vivo. The investigators will also test the hypothesis that clones of virus-specific CTL can persist for the entire course of the virus infection. Additionally, they will determine whether the MHC of the rhesus macaque can play a role in resistance to SIV infection in vivo. Finally, they will investigate whether opiates can influence the generation of AIDS virus-specific CTL or helper T lymphocyte (HTL) responses during the course of AIDS virus infection in vivo. These studies will be carried out using blood samples obtained from an ongoing NIH-supported study aimed at determining how opiate-dependency alters progression of AIDS induced by SIV smm9 in 40 rhesus macaques. In Specific Aim 1 they will test the hypothesis that the nef-specific CTL response selects for new viral variants and that these new variants escape CTL recognition. They have recently generated preliminary data indicating that CTLs exert considerable selective pressure on nef, whereas selective pressure on env CTL epitopes was more relaxed. In Specific Aim 2 they will test the hypothesis that clones of CTL generated early in the course of SIV infection persist for the entire course of the disease. Dr. McMichael's group have preliminary data suggesting that clones of T cells can persist during SIV infection. This is somewhat contrary to previous findings. In Specific Aim 3 they will test the hypothesis that certain MHC alleles can influence the course of SIVsmm9 infection in vivo. Since products of the MHC genes bind pathogen-derived peptides and present them to T cells, it has been suggested that these highly polymorphic molecules might influence how an individual makes a response to the AIDS virus. Recent studies have indicated that certain HLA molecules may play an important role in long-term non-progressors. In Specific Aim 4, they will test the hypothesis that opiates can influence CTL or HTL responses which can, in turn, determine the course of disease after infection. Although evidence exists for the role CTLs and HTLs in HIV infection, it has been difficult to carry out long term studies in individuals in which time of infection, and dose and nature of the virus are known in a relevant animal model. In this cohort of animals they will be able to determine whether opiates can influence the cellular immune response to the AIDS virus.